ABSTRACT Radiation is an important component of therapy for locally advanced pancreatic cancer as evidenced by its ability to improve both local control and survival as well as by the finding that 1/3 of pancreatic cancer patients die as a result of local disease progression (1-3). Despite the benefits of radiation therapy for pancreatic cancer, further improvements are urgently needed. Radiation kills cells by induction of DNA double strand breaks (DSBs) and repair of these DSBs is a mechanism of tumor cell resistance to radiation (4, 5). Thus, in the current proposal we plan to selectively sensitize pancreatic cancer cells and tumors to radiation by inhibition of DNA repair by the DNAPK inhibitor M3814. We anticipate that M3814 will delay the repair of radiation-induced DSBs resulting in persistent and lethal DNA damage in tumor cells. In addition, we hypothesize that M3814 in combination with radiation will increase innate immunity in tumor cells that will contribute to additional tumor cell lethality.